WO2002023541A1 - Dérivés de zofimarin présentant un noyau oxazépame - Google Patents

Dérivés de zofimarin présentant un noyau oxazépame Download PDF

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WO2002023541A1
WO2002023541A1 PCT/JP2001/007925 JP0107925W WO0223541A1 WO 2002023541 A1 WO2002023541 A1 WO 2002023541A1 JP 0107925 W JP0107925 W JP 0107925W WO 0223541 A1 WO0223541 A1 WO 0223541A1
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group
meo
methyl
compound
pharmacologically acceptable
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PCT/JP2001/007925
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Japanese (ja)
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Satoru Kaneko
Masami Arai
Takuya Uchida
Toshiyuki Konosu
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Sankyo Company, Limited
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Priority to AU2001286208A priority Critical patent/AU2001286208A1/en
Publication of WO2002023541A1 publication Critical patent/WO2002023541A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D267/02—Seven-membered rings
    • C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D267/10—Seven-membered rings having the hetero atoms in positions 1 and 4 not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to a zofimarin derivative having excellent antifungal activity, a pharmacologically acceptable ester thereof, a pharmacologically acceptable salt thereof, a pharmaceutical composition containing them as an active ingredient (particularly an antifungal agent), Use of a derivative, ester or salt thereof for producing a pharmaceutical composition, or a disease (particularly fungal infection) in which a pharmacologically effective amount of the derivative, ester or salt is administered to a warm-blooded animal (particularly human). ) For prevention or treatment.
  • compounds considered to have the same action mechanism as the zofimarin derivative according to the present invention include zofimarin, a natural product described in JP-A-62-40292. Others are described in JP-A-6-157582, JP-A-9-508144, JP-T-11-502188, W098 / 15178, W099 / 09974 and Gazette of W099 / 09975. And sonoredarine derivatives.
  • none of them are fully satisfactory as pharmaceuticals (antifungal agents) in terms of antifungal activity and pharmacokinetics.
  • problems such as a narrow antifungal spectrum, a short half-life in blood, a high protein binding rate, and low water solubility.
  • WO99 / 58512 discloses a zofimarin derivative having a morpholine structure in a side chain.
  • these derivatives are mainly fungi of the genus Candida It has only antifungal activity against and its pharmacokinetics are still not fully satisfactory.
  • the production of these derivatives from zofimarin or solderin derivatives may require a step of converting the methoxy group on the pyranose ring into a hydroxyl group by complicated microbial conversion using a special microorganism. Impractical.
  • this publication also describes a method for producing a morpholine ring by separately constructing the morpholine ring and then binding it to sodalysine, but this method involves a complicated glycosylation reaction using special reaction conditions. Is required, the reaction yield is low, and there is a by-product of a stereoisomer.
  • the compounds of the present invention also have antifungal activity against non-Candida fungi, for example, fungi of the genus Tarticococcus, exhibit excellent pharmacokinetics in vivo, and are relatively easy to synthesize. There is something.
  • An object of the present invention is to provide fungi, especially fungi of the genus Candida including strains that are insensitive to azole antifungal agents, and fungi of the genus Candida, such as those of the genus Cryptococcus.
  • An object of the present invention is to provide a zofimarin derivative which has an action, exhibits good pharmacokinetics in vivo, is highly safe, has excellent physicochemical properties, and is relatively easy to synthesize.
  • the present inventors have proposed and synthesized a zofimarin derivative having an oxazepane ring, and the zofimarin derivative according to the present invention has excellent antifungal activity.
  • the present invention was found to be useful as a fungicide, and the present invention was completed.
  • the present invention was found to be useful as a fungicide, and the present invention was completed.
  • R 1 represents a formyl group or a cyano group.
  • R 2 and R 3 independently represent a hydrogen atom, a hydroxyl group, a —C 6 alkyl, or a —alkoxy group.
  • R 4 is a hydrogen atom, an alkyl group (having 1 to 3 You may. .), C 2 -C 6 alkenyl group (but it may also have from 1 to 3 of substituents ⁇ described later), C 2 - C 6 alkynyl group (having 1 to 3 of substituents ⁇ described later ⁇ C 3 -C i, a cycloalkyl group (may have 1 to 3 substituents
  • Substituents cd or a halogen atom, Shiano group, a nitro group, the formula - group (R 5 having the OR 5 is a hydrogen atom, - alkyl, (: halogenated alkyl group, or C 6 - to C 1 0 Ariru group shown), the formula -. S ( 0) n - group (R 6 with R 6 is a hydrogen atom, C "C 6 ⁇ alkyl group, d-Ce halogenated alkyl group, or -. indicates Ariru group, n is an integer of 0 to 2), C 3 -. 0 cycloalkyl group (which may have 1 to 3 of substituents ⁇ described later), -..
  • cycloalkenyl group (substituent which will be described later] May have from 1 to 3), a heterocyclyl group (may have 1 to 3 substituents as described below.), A Ce-Ci. Aryl group (to be described later) And a heteroaryl group (which may have 1 to 3 substituents ⁇ , which will be described later; ').
  • the substituents are (C 6 alkyl group, halogen atom, cyano group, nitro group, C-C 6 halogenated alkyl group, oxo group, group having the formula -OR 7 (R 7 is a hydrogen atom, C A 6- alkyl group, a (C 6 -perogenated alkyl group, or a C 6- .
  • R 9 is a hydrogen atom, - C 6 alkyl group , (: Factory halogenated alkyl group, or a group selected from the group consisting of C 6- (indicating a 10 aryl group, and n ′ is an integer of 0 to 2).
  • R 1 1 represents a hydrogen atom, an alkyl group, or a halogenated alkyl le group, eta ' Is an integer of 0 to 2.
  • R 1 1 represents a hydrogen atom, an alkyl group, or a halogenated alkyl le group, eta ' Is an integer of 0 to 2.
  • R 1 1 represents a hydrogen atom, an alkyl group, or a halogenated alkyl le group, eta ' Is an integer of 0 to 2.
  • R 1 1 represents a hydrogen atom, an alkyl group, or a halogenated alkyl le group, eta ' Is an integer of 0 to 2.
  • the ⁇ alkyl group '' in R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R′R 1 , the substituted part j3 and the substituted part ⁇ is a linear or A branched saturated hydrocarbon group Good, - as the c 6 alkyl groups such as methyl, Echiru, propyl, isopropyl, heptyl, Isopuchiru, S - butyl, t - heptyl, pentyl, S - pentyl, Isopenchinore, 2 - Mechinorebuchinore, Neopenchinore, 1 - Echino Repropinole, hexinole, 4-methylpentylsisohexyl), 3-methylpentyl, 2-methylpentyl, 1-methylpentyl (S-hexyl), 3,3-dimethylbutyl, 2,2-dimethyl Buty
  • the ⁇ alkoxy group '' in R 2 and R 3 refers to a linear or branched alkoxy group, and -C 6 alkoxy group includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy.
  • it is a C 4 C 4 alkoxy group, more preferably an -alkoxy group, most preferably a methoxy group.
  • alkenyl group for R 4 means a ⁇ -chain or branched alkenyl group having one or two double bonds, and examples of the C 2 -C 6 alkenyl group include etheninolene, 2 -Propenyl, trimethinole-2-propenyl, 2-methyl-2-propenyl, 2-ethyl-2-propeninole, 2-butul, 1-methyl-2-butenyl, 2- Methyl-2-butenyl, 3-methyl-2-butenyl 1-ethyl-2-butenyl, 3-butenyl, 1-methyl_3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1 -Ethyl-3-butenyl, 2-penteninole, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-penteninole, 1-methynole-3-pentenyl, 2-methyl-3-pentenyl, 4-Methyl
  • alkynyl group refers to a linear or branched alkynyl group having one or two triple bonds, and examples of the C 2 -C 6 alkynyl group include ethynyl and 2- Propynyl, 1-methyl-2-propynyl, 1,1-dimethyl-2-probuyl, 2-butynole, 1-methinole-2-butyn ⁇ -ethynole-2-butynyl, 3-butyn-1-methine Nole-3-butynyl, 2-methyl-3-butynyl, 1-ethynole-3-pentinole, 2-pentynole, tomethyl-2-pentynyl, 2-methyl-2_pentynyl, 3-pentynyl, 1-pentynyl Mechinore-3-pentinole, 2-methinole 3-pentinole, 4-pentinole, 1-methinole-4-pentinole, 2-methinole-4_pentinole, 2-methin
  • the “aryl group” in R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and the substitution ⁇ refers to an aromatic hydrocarbon ring group, Ce—.
  • aryl groups include phenyl, 1-naphthyl and 2-naphthyl, and phenyl is preferred.
  • the “halogenated alkyl group” in R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , 11 , the substituted part and the substituted part ⁇ means that the hydrogen atom of the above-mentioned alkyl group is 1 to A monovalent group substituted by three halogen atoms.
  • C Factory C 6 Examples of the halogenated alkyl group include, for example, trifluoromethyl, trichloromethyl, difluoromethyl, dimethoxymethyl, dibromomethyl, fluoromethyl, 2, 2 , 2-Trifluoroethyl, 2,2,2-Trichloroethinole, 2-Promoechinolle, 2-Chloroechinolle, 2-Funoleochinolle, 2-Edoetinolle, 3-Chloe-mouth propinolle, 4_Fluorobuchinolle, 6_Yo I-hexyl and 2,2-dibro
  • the “cycloalkyl group” in R 4 and the substituent means a cyclic saturated aliphatic hydrocarbon group which may be condensed, and-.
  • Examples of the cycloalkyl group include cyclopropinole, cyclobutynole, cyclopentinole, cyclohexanol, cycloheptyl, cyclootatyl, norbornolenyl, and adamantyl, and preferably a C 3 -cycloalkyl group.
  • the “cycloalkenyl group” in R 4 and the substituent ⁇ refers to a condensed or cyclic unsaturated aliphatic hydrocarbon having one double bond, and C 3 -C i Q the cycloalk Keninore groups such Shikuropuro Bae sulfonyl, Shikurobuteninore, cyclopent alkenyl, cyclohexenyl, cyclohexane cycloheptenyl, ⁇ Pi norbornene - Le a can and Ageruko, preferably a C 3 -C 6 cycloalkenyl group.
  • the position of the double bond in R 4 is preferably such that the nitrogen in perhydro-1,4-oxazepine (seven-membered ring) does not form an enamine structure with respect to nitrogen.
  • heterocyclyl group in R 4 and the substituents means a 4- to 10-membered saturated heterocyclic group having 1 to 3 hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. , For example, oxetanyl, cetanyl, azetidinyl, etc.
  • 5-membered heterocyclyl groups such as tetrahydrofuryl, thiolanyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, isosoxazolidinyl, thiazolidinyl, isothiazolidinyl and the like; 5-membered heterocyclyl groups; Examples include 6-membered heterocyclyl groups such as morpholinyl and thiomorpholinyl; 7-membered heterocyclyl groups such as homopiperazinyl; and 10-membered heterocyclyl groups such as oxecane and azecan, and preferably 5 to 6-membered heterocyclyl. Group.
  • Heteroaryl group in R 4 and the substituted moiety means a monocyclic or polycyclic aromatic group having 1 to 3 hetero atoms selected from the group consisting of oxygen, nitrogen and sulfur.
  • a 5-membered monocyclic ring such as furyl, phenyl, pyrenyl, pyrazolyl, imidazolyl, oxazolyl, isoxoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxdiazolyl, triazolyl, thiadiazolyl, triazolyl, etc.
  • Heteroaryl 6-membered monocyclic heteroaryls such as pyridyl, pyridazinyl, pyrimidinyl, and virazinyl; isobenzofurinole, benzofurael, isobenzothiophenolene, benzothiopheninole, indolizinyl, isoindolyl, indolyl, benzoxazolyl , 9 members such as benzothiazolyl Polycyclic heteroaryl; and 10-membered polycyclic heteroaryl such as chromenyl, isoquinolyl, quinolyl, quinazolinyl and the like, preferably a monocyclic heteroaryl group, more preferably furyl or Chenyl.
  • 6-membered monocyclic heteroaryls such as pyridyl, pyridazinyl, pyrimidinyl, and virazinyl
  • isobenzofurinole benzofurael,
  • the “halogen atom” in the substitution ⁇ :, the substitution] 3 and the substitution ⁇ include, for example, a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, preferably a chlorine atom or a bromine atom. Is an atom.
  • the substituents may be the same or different from each other. Ray.
  • the “pharmacologically acceptable ester” in the compound according to the present invention refers to a pharmaceutical compound in the carboxyl group in the general formula (I) and the hydroxyl group in the side chain of the perhydro-1,4-oxazepine structure. And preferably an ester which is hydrolyzed in vivo at a carboxyl group in the general formula (I) and a hydroxyl group in a side chain of the perhydro-1,4-oxazepine structure. It is.
  • ester undergoing hydrolysis in vivo refers to an ester that is cleaved in vivo by a chemical or biological method such as hydrolysis to form the zofimarin derivative or a salt thereof according to the present invention.
  • the ester residue of the carboxyl group in the general formula (I) is, for example,-. Alkyl group, - 2 ⁇ Li 'Lumpur groups, C 2 -.
  • Asiloxy Examples include an alkyl group, (: 2- . Alkoxycarbonyloxyalkyl group, phthalidyl group, and 2-oxo-1,3-dioxolen-4-ylmethyl group.
  • C 10 alkyl group examples include: as C 1 2 Ariru groups - such as methyl, Echiru, propyl, Isopuchiru, hexyl, Okuchiru, and decanyl can be mentioned, preferably a alkyl group, and most preferably methyl or Echiru C 6.
  • Is for example, phenyl, biphenyl, and naphthyl, preferably phenyl or biphenyl, and most preferably phenyl.
  • -Asyloxyalkyl groups include, for example, bivaloyloxymethyl, Isobutyryloxymethyl, 1- (isobutyryloxy) ethyl, acetoxymethyl, 1- (acetoxy) ethino ,
  • Hexyl carbonyl O carboxymethyl to 1 methylcyclohexane include a 1-Mechirushiku port pentylcarbonyl O Carboxymethyl C 2 -.
  • alkoxycarbonyl O The alkoxyalkyl groups such as t- butoxy carboxymethyl Interview Ruo Kishime chill, 1 -(Methoxycarbonyloxy) ethyl, 1_ (ethoxycarbonyloxy) ethyl, 1- (isopropoxycarbonyloxy) ethyl, l- (t-butoxycarbonyloxy) ethyl, 1_ (3_pentyloxy) Carbonyloxy) ethyl, 1- (cyclohexylcanoleboninoleoxy) ethyl and 1- (cyclopentylcarbonyloxy) ethyl, among these ester residues, preferably piperoyloxymethyl 1- (ethoxycarbonyloxy) ethyl, 1- (isopropoxycarbonyloxy) ethyl, 1- (3-pentyloxycarbonyloxy) ethyl or 1- (cyclohexylcarbonyloxy) ethyl, most
  • ester residues in the hydroxyl group in the side chain of the perhydro-1,4-oxazepine structure include, for example, formyl, acetyl, propionyl, butylyl, isobutylinole, pentanoyl, bivaloyl, norelyl, isovaleryl, octanolyl , Nonanoyl, Decanoyl, 3-Methylnonanoyl, 8-Methinolenonanoyl, 3-Ethyloctanyl, 3,7-Dimethyloctanoyl, Pendecanoyl, Dodecanoyl, Tridecanoyl, Tetradecanoinole, Pentadecanoyl, Hexadecanoyl , 1-methylpentadecanoyl, 14-methylpentadecanoyl, 13,13-dimethyltetradecanoyl, heptadecanoyl, 15-methyl
  • the ⁇ pharmacologically acceptable salt '' in the compound according to the present invention means a carboxyl group in the general formula (I) and a basic group in the perhydro-1,4-oxazepine structure, And commonly used salts.
  • Such salts at the carboxyl group in the general formula (I) include, for example, alkali metal salts such as sodium salt, potassium salt and lithium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum Salts, iron salts, zinc salts, copper salts.
  • Metal salts such as salts, nickel salts and cobalt salts; inorganic salts such as ammonium salts; t-otatylamine salts, dibenzylamine salts, morpho, phosphorus salts, gnorecosamine salts, phenylglycine alkyls Ester salt, Ethylenediamine salt, N-Methyldalcamine salt, Guanidine salt, Getylamine salt, Triethylamine salt, Dicyclohexylamine salt, ⁇ , ⁇ '-Dibenzylethylenediamine salt, Black salt, Procaine salt , Diethanolamine salt, ⁇ ⁇ ⁇ ⁇ -benzyl- ⁇ -phenethylamine salt, piperazine Organic amine salts such as salts, tetramethylammonium salts, and tris (hydroxymethyl) aminomethane salts.
  • inorganic salts such as ammonium salts
  • salts in the basic group in the perhydro-1,4-oxazepine structure include, for example, hydrogen halides such as hydrofluoride, hydrochloride, hydrobromide and hydroiodide.
  • Acid salts include, for example, hydrogen halides such as hydrofluoride, hydrochloride, hydrobromide and hydroiodide.
  • Acid salts include, for example, hydrogen halides such as hydrofluoride, hydrochloride, hydrobromide and hydroiodide.
  • Acid salts such as nitrates, perchlorates, sulfates, and phosphates
  • salts of lower alkylsulfonic acids such as methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate
  • Amylate salts such as arylsulfonate, ordinate, glutamate such as enesulfonate,
  • the compound according to the present invention may absorb moisture when left in the air or recrystallize, and may form adsorbed water or form a hydrate.
  • the zofimarin derivative and the pharmaceutically acceptable ester thereof and the pharmaceutically acceptable salt thereof according to the present invention each include such a hydrate.
  • the compounds according to the invention may absorb certain other solvents and form solvates.
  • the zofimarin derivative and the pharmacologically acceptable ester thereof and the pharmacologically acceptable salt thereof according to the present invention each include such a solvate.
  • the compounds of the present invention also include various isomers.
  • R 2 , R 3 and R 4 which are side chains of the perhydro-1,4-oxazepine structure in the general formula (I) also have an asymmetric carbon or a carbon-carbon double bond. Therefore, various stereoisomers exist in the compound according to the present invention. Each of them or a mixture in any proportion thereof is encompassed by the present invention.
  • Such a stereoisomer may be obtained by using a stereospecific raw material compound, or by the ability of synthesizing the compound of the present invention using an asymmetric synthesis or asymmetric induction technique, or by using the synthesized compound of the present invention. If desired, it can be obtained by division using a conventional optical resolution method or separation method.
  • R 2 and R 3 independently represent a ⁇ -(: 6 alkyl or alkoxy group, a sophistical derivative thereof, a pharmaceutically acceptable ester thereof, or a pharmaceutically acceptable salt thereof,
  • R 2 represents a (C: alkyl group at position 7 of the perhydro-1,4-oxazepine structure
  • R 3 represents a -C 6 alkoxy group at position 6 of the perhydro-1,4-oxazepine structure.
  • R 2 represents an alkyl group at position 7 of the perhydro-1,4-oxazepine structure
  • R 3 represents -C at position 6 of the perhydro-1,4-oxazepine structure.
  • R 2 represents a Cf C 2 alkyl group at position 7 of the perhydro-1,4-oxazepine structure
  • R 3 represents a C Factory C 2 alkoxy group at position 6 of the perhydro-1,4-oxazepine structure Or a pharmacologically acceptable ester thereof or a pharmacologically acceptable salt thereof,
  • a zofimarin derivative or a pharmaceutically acceptable derivative thereof wherein R 2 represents a methyl group at position 7 of the perhydro_1,4-oxazepine structure, and R 3 represents a methoxy group at position 6 of the perhydro-1,4-oxazepine structure.
  • Ester or a pharmacologically acceptable salt thereof
  • R 4 force hydrogen atom, C! -Alkyl group (may have 1 to 3 substituents ⁇ ), C 3 -C 6 alkenyl group (having 1 to 3 substituents) ), A C 3 _C 6 alkynyl group (which may have 1 to 3 substituent (s)), a C 3 -C 10 cycloalkyl group (which may have 1 to 3 substituent (s)). ), C 3 -C 10 cycloalkenyl group (substituted, may have 1 to 3) 3), or C 6 -C 10 aryl group (substituted 1 to 3 substituted ⁇ ) A zofimarin derivative or a pharmaceutically acceptable ester thereof, or a pharmaceutically acceptable salt thereof,
  • R 4 force hydrogen atom, -alkyl group (may have 1 to 3 substituents), C 3 -C 6 alkenyl group (even if it has 1 to 3 substituents ⁇ ) ), C 3 _C 6 alkynyl group (may have one substituent,), C 3- .
  • a cycloalkyl group (which may have one substituent 3), a C 3 -C 10 cycloalkenyl group (which may have one substituent), or Ce-C ⁇ .
  • An aryl group (which may have one substituted ⁇ ), a pharmacologically acceptable ester or a pharmacologically acceptable salt thereof,
  • R 4 is selected from the group consisting of: (a 6 alkyl group (may have 1 to 3 substituents ⁇ )) or a C 3 -C 6 alkenyl group (1 to 3 substituents ⁇ A zofimarin derivative or a pharmacologically acceptable ester thereof, or a pharmacologically acceptable salt thereof,
  • R 4 is a C factory C 2 alkyl group (which may have one substitution ⁇ ), a zofimarin derivative or a pharmaceutically acceptable ester thereof, or a pharmaceutically acceptable salt thereof, ⁇
  • R. 4 may have one methyl group (substituent alpha.
  • a cycloalkenyl group (which may have 1 to 3 substituents
  • substituent ⁇ is, (3 _ cycloalkyl group (substituent] 3 which may have 1 to 3), C 3 -... A cycloalkenyl group (substituent j3 1 to 3 Aryl group (may have 1 to 3 substituents ⁇ ), and Zofi 'marine derivative or a pharmaceutically acceptable ester thereof or a pharmaceutically acceptable ester thereof which represents a group selected from the group consisting of a heteroaryl group (which may have 1 to 3 substituent (s) Y). Salt,
  • the substituted ⁇ is a C 3 -C 6 cycloalkyl group (may have one substituted jS), a C 3 -C 6 cycloalkenyl group (having one substituted
  • a aryl group (which may have 1 to 3 substituents ⁇ ) and a heteroaryl group (which may have 1 to 3 substituents).
  • the substituted moiety may be a C 6 -C 10 aryl group (may have 1 to 3 substituents ⁇ ), and a heteroaryl group (having 1 to 3 substituents ⁇ ).
  • substitution ⁇ represents a phenyl group (even if it has one substitution ⁇ ).
  • substitution ⁇ is an alkyl group, a halogen atom, a C 4 alkyl halide group, and a group having the formula —OR 1 °
  • R 1 is a C 4 alkyl group or a halogenated alkyl group.
  • substitution ⁇ is a -C 2 alkyl group, a halogen atom, a C 2 halogenated alkyl group, and a group having the formula -OR 1 ° (R 1 () is a -C 2 alkyl group, or -C 2 And a pharmacologically acceptable ester thereof, or a pharmacologically acceptable salt thereof, which represents a group selected from the group consisting of:
  • ' 1 is selected from (1)' and (2), (3) and (7) forces ⁇ R 2 and R 3 are selected, and (8) ) Through (16), R 4 is selected, (17) through (26), the substitution ⁇ is selected, (27) through (29) the substitution from the force) S, and (30) through (30).
  • Compounds obtained by selecting and combining the force-substitution y are also suitable.
  • the compounds of the present invention include, for example, the zofimarin derivatives described in Tables 1 to 11, their pharmacologically acceptable esters, and their pharmacologically acceptable salts. However, the present invention is not limited to this compound. Incidentally, the zofimarin derivatives described in Tables 1 to 11 have the general formula ().
  • Azt azetidininole, Ac: acetinole, Bu: butinole, cBu: cyclobutyl, tBu: t-butyl, Bz: benzyl, CH0: formyl, Cim: cinnamyl, CN: cyano, Et: Echinole, Fur: Furinole, cHp: Cycloheptinole, cHx: Cyclohexyl, Imid: .mididolyl, Ind: Indolyl, Isox: Isoxazolyl, Me: Methyl, Np: Naphthyl, cOc: Cyclooctyl, Oxa: Oxazolyl, Ph : Phenyl, Pip: pyridyl, cPn: pentyl, Pr: propyl, cPr: propyl, iPr: isopropyl, Pym: pyrimidinyl,
  • Preferred compounds among the compounds exemplified in the above table include the following compounds.
  • 11-7 3D is one of the living things
  • the compound having the general formula (I) of the present invention can be produced according to the following method.
  • a compound having the general formula (I) of the present invention in which R 1 is a formyl group and R 2 is a perhydro-1,4-oxazepine structure, starting from sordarin, one of the zofimarin derivatives, is used as a starting material.
  • R 4 a represents the above R 4 and as defined (except when R 4 is hydrogen atom), the R '1 is a protecting group, X 1 is shows a protected formyl group .
  • the protecting group R' 1 refers to an ester protecting group generally used for protecting carboxylic acids in organic synthetic chemistry (for example, TW Greene et al., Protective Groups in Organic Synthesis, 2nd Edition). , John Wiley & Sons, Inc.
  • Cyclic alkyl group Cyclic propylmethyl, Cyclic butylmethyl, Cyclic pentinolemethinole, Cyclohexinolemethinole, Cycloheptinolemethinole, Cyclooctylmethyl, Cyclononylmethyl, Cyclodecylmethyl, (Cyclopropyl) ethylinole, (Cyclopuchinole) ( 4- cycloalkylalkyl group; phenyl, tolyl) may be substituted such as ethynole, (pent pentinole) ethyl, (hex hexinole) ethyl, (cycloheptyl) ethyl, (cyclooctyl) ethyl group.
  • an optionally substituted c 6 -c 10 aryl group such as a naphthyl group; an optionally substituted heterocyclic group such as a tetrahydroviranyl, tetrahydrofuryl or pyridyl group; benzyl, phenethyl, 3- Phenylpropyl, 1-methyl-1-phenylethyl, C that may be substituted, such as hydrhydryl, trityl, fluorenyl, fluorenylmethyl, 9-anthrylmethinole, trimethylbenzyl, bromobenzyl, nitrobenzyl, methoxybenzyl or dimethoxybenzyl group ?
  • protected with formyl group X 1 shows a formyl group protected by a protecting group commonly used for the protection of the aldehyde compounds in synthetic organic chemistry (for example, TW Greene et al, Protective Groups in Organic Synthesis, 2nd Edition, John Wiley & Sons, Inc. (1991)), the type of which is not particularly limited.
  • a formyl group protected with a cyclic or acyclic acetal, a cyclic or acyclic thioacetal is protected.
  • Formyl group formyl group protected with cyclic or acyclic monothioacetals, formyl group protected as cyanohydrin (1-cyano-1-hydroxymethyl group optionally protected with hydroxyl group), hydrazone Formyl group protected as imine, formyl group protected as imine, formyl group protected as oxazolidine or protected as imidazolidine Formyl group and the like can be mentioned. .
  • This step is a step of producing a compound (III) by protecting the carboxyl group of the compound (II).
  • Solderin which is the starting compound (II), can be obtained by the method described in von D. Hauser et al. Helvetica Chimica Acta,. 54, pp. 1178-1190 (1971) or a method analogous thereto.
  • This step is achieved by a carboxyl group protection reaction commonly used in organic synthetic chemistry (eg, TW 'Greene, Protective Groups in Organic Synthesis, 2nd Edition, John Wiley & Sons, Inc. (1991)) reference). For example, it is performed as shown in the following (1) and (2).
  • the protected compound (III) can be produced by reacting the compound (II) with an alkylating agent in a solvent under basic conditions.
  • Arukiruihi agent formula R '1 Z 1 (wherein, R' 1 represents the same meaning as above, Z 1 is a halogen atom or a leaving group to replace it) is a compound represented by, for example, chloride , Bromide, iodide and other halides; or methanesulfonic acid ester, trifluoromethanesulfonic acid ester, toluenesulfonic acid ester, etc. And sulfonic acid esters. Of these, halides (especially bromides) are preferred.
  • the solvent examples include hydrocarbons such as hexane, cyclohexane, benzene, and toluene; halogenated hydrocarbons such as dichloromethane and dichloroethane; ketones such as acetone and 2-propanone; and sulfoxides such as dimethyl sulfoxide.
  • Amides such as N, N-dimethylformamide; nitriles such as acetonitrile; and dimethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxetane And the like, and preferably amides (particularly N, N-dimethylformamide).
  • the base is not particularly limited as long as it is a base used in organic synthetic chemistry.
  • alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, and sodium hydrogen carbonate
  • triethylamine, disopropylethyl Organic amines such as dimethylamine, dicyclohexylamine, pyridine, norethidine, 4- (dimethylamino) pyridine, diazabicyclopentadecene and diazabicyclononene
  • alkali metal alcoholates such as sodium methoxide.
  • it is an alkali metal carbonate (particularly sodium carbonate).
  • the reaction temperature is usually in the range of o ° C to the boiling point of the solvent (preferably in the range of o ° C to room temperature), and the reaction time depends mainly on the type of the introduced protecting group. Time (preferably 0.5 to 6 hours).
  • the protected compound (III) can also be produced by reacting the compound (II) with a diazo compound in a solvent.
  • diazo compound for example, diazomethane, trimethylsilyldiazomethane, diphenyldiazomethane and the like are preferred, and diphenyldiazomethane is preferred.
  • the solvent examples include halogenated hydrocarbons such as dichloromethane and dichloroethane; ketones such as acetone and 2-propanone; esters such as ethyl acetate; anolecones such as methanol and earth tanol; Examples thereof include ethers such as tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxetane, and preferred are aethenoles (particularly, tetrahydrofuran).
  • the reaction temperature is usually in the range of 0 ° C. to the boiling point of the solvent (preferably 0 ° C. to room temperature), and the reaction time varies depending mainly on the type of the introduced protecting group. Time (preferably 0.5 to 6 hours).
  • compound (III) can be collected from the reaction mixture by a usual method. For example, after neutralization, the reaction mixture or a solvent obtained by distilling off the solvent of the reaction mixture is mixed with an organic solvent immiscible with water, washed with water, and the solvent is distilled off. If necessary, the obtained compound (III) can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • This step is a step of producing a compound (IV) by protecting the formyl group of the compound (III) obtained in the A-1 step.
  • This step is achieved by a formyl group protection reaction commonly used in organic synthetic chemistry (eg, TW Greene, Protective Groups in Organic Synthesis, 2nd Edition, John Wiley & Sons, Inc. (1991)) reference). For example, this is performed as shown below.
  • a formyl group protection reaction commonly used in organic synthetic chemistry (eg, TW Greene, Protective Groups in Organic Synthesis, 2nd Edition, John Wiley & Sons, Inc. (1991)) reference). For example, this is performed as shown below.
  • the formyl group is protected as an acetal, it is usually achieved by reacting the aldehyde compound (III) with an alcohol conjugate in a solvent under acidic conditions.
  • Examples of the solvent used include alcohols such as methanol, ethanol, ethylene glycol, and 1,3-propanediol; hydrocarbons such as hexane, cyclohexane, benzene, and
  • the alcohol conjugate used preferably includes methanol, ethanol, ethylene glycol, 1,3-propanediol, benzyl alcohol, and the like, and more preferably, ethylene dalicol.
  • Examples of the acid to be used include mineral acids such as hydrochloric acid and sulfuric acid; sulfonic acids such as P-toluenesulfonic acid, methanesulfonic acid and camphorsulfonic acid; and carboxylic acids such as trinoleoacetic acid. Of these, sulfonic acids (particularly p-toluenesulfonic acid) are preferred.
  • a dehydrating agent may be co-present in order to promote the reaction.
  • the dehydrating agent include zeolites such as molecular sieves; acetals such as 2,2-dimethoxypropane; enol ethers such as 2-methoxypropene; orthoesters such as methyl orthoformate; Active phosphoric acid derivatives such as nilin and oxychlorinated phosphorus; silylating agents such as chlorotrimethylsilane and trimethylsilyl trifluoromethanesulfonate; Of these, orthoesters (particularly methyl orthoformate) are preferred.
  • the reaction temperature is usually in the range of 0 ° C to the boiling point of the solvent (preferably 0 ° C to room temperature).
  • the reaction time varies depending on the alcohol conjugate used, but is usually 0.1 to 24 hours (preferably 0.5 to 2 hours).
  • compound (IV) can be collected from the reaction mixture by a usual method. For example, after neutralization, an organic solvent which does not mix with water is added to the reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washing with water and distilling off the solvent.
  • the obtained compound (IV) can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • This step is a step of oxidizing the compound (IV) obtained in the step A-2 to open the tetrahydrosilane ring to produce a dialdehyde compound (V).
  • This step is achieved by reacting compound (IV) with an oxidizing agent in a solvent.
  • the solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting compound (IV) to some extent. Examples thereof include water; alcohols such as methanol and ethanol-propanol; and petroleum ether.
  • Hydrocarbons such as hexane, pentane, hexane, and cyclohexene, benzene, and toluene; halogenated hydrocarbons such as dichloromethane, chlorophonolem, and 1,2-dichloroethane; and esterols such as ethyl acetate; Ethers such as ether, 1,2-dimethoxetane and tetrahydrofuran; nitriles such as acetonitrile; amides such as ⁇ , ⁇ -dimethylformamide and ⁇ , ⁇ -dimethylacetamide; Ketones such as acetone and 2-butanone; and mixtures thereof, of which water, alcohol And mixtures thereof, more preferably a mixture of methanol and water.
  • halogenated hydrocarbons such as dichloromethane, chlorophonolem, and 1,2-dichloroethane
  • esterols such as ethyl a
  • the oxidizing agent used includes, for example, perhalates such as sodium metaperiodate, lead salts such as lead tetraacetate, and permanganates such as permanganate potassium lime. Preferred are halogenated salts and lead salts, and more preferred are perhalated salts (particularly sodium metaperiodate).
  • the amount of the oxidizing agent to be used is generally 1 to 10 molar equivalents (preferably 2 to 6 molar equivalents) relative to the starting compound (IV).
  • the reaction may be carried out by adding a base to prevent the reaction solution from becoming acidic.
  • a base include hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate and carboxylate salts such as sodium acetate, and among them, hydrogen carbonates (particularly sodium hydrogen carbonate) are preferable.
  • the amount of the base to be used is usually 0.1 to 5 molar equivalents relative to the starting compound (IV).
  • the reaction temperature is usually in the range of ⁇ 40 ° C. to the boiling point of the solvent, preferably 0 ° C. to room temperature.
  • the reaction time varies depending on the type of the oxidizing agent and the reaction temperature, but is usually in the range of 0.2 to 48 hours, preferably 2 to 15 hours.
  • compound (V) After completion of the reaction, compound (V) can be collected from the reaction mixture by a usual method. For example, after neutralization, an organic solvent which does not mix with water is added to the reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washing with water and distilling off the solvent. However, since the formyl group of the dialdehyde compound (V) forms a hydrate or forms a hemiacetal within or between molecules, the dialdehyde compound (V) usually has the formyl group. It is obtained as an equilibrium mixture of compounds in various association states. The obtained compound (V) can be purified to some extent by a conventional method, if necessary, for example, by reprecipitation or by mouth chromatography, but it is usually usable in the next step without further purification. it can.
  • the dialdehyde compound (V) obtained in the step A-3 is reductively reacted with an amine compound having the formula to produce a 7-membered ring compound (VI). .
  • This step is Jiarudehi de compound (V), and Amin compound having the formula R 4 a NH 2, in a solvent, usually in the presence of an acid, is achieved by reacting with a reducing agent.
  • a reducing agent a reducing agent for reacting with a reducing agent.
  • the dialdehyde compound (V) the crude product obtained in Step A-3 can be used as it is.
  • the amine compound having the formula R 4 a NH 2 a commercially available compound is mainly used, but when there is no commercially available compound, it can be obtained by a method generally used in organic synthetic chemistry.
  • the compound R 4a Z 1 (Z 1 is the same as that described in the description (1) of Step A-1 above) can be obtained by a corresponding method commercially available or obtained by a method generally used in organic synthetic chemistry. Significance can be obtained as follows.
  • the solvent used in 1) in the above formula includes, for example, hydrocarbons such as hexane, cyclohexane, benzene, and toluene; halogenated hydrocarbons such as dichloromethane and dichloroethane; Ketones such as 2, 2-propanone; sulfoxides such as dimethyl sulfoxide; amides such as ⁇ , ⁇ ⁇ ⁇ ⁇ -dimethylformamide Nitriles such as acetonitrile; and ethers such as getyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxetane, and the like. Amides (particularly, ⁇ , ( ⁇ ⁇ ⁇ ⁇ -dimethylformamide).
  • the reaction temperature varies depending mainly on the solvent used, but is usually in the range of room temperature to 150 ° C, and preferably in the range of room temperature to 100 ° C.
  • the reaction time in the above formula 1), the compound R ⁇ Z 1 and varies the solvent used Te cowpea is generally 3 0 minutes to 1 0 hours, preferably 1 to 4 hours.
  • the corresponding N-substituted phthalimid compound can be collected from the reaction mixture by a conventional method. For example, after neutralization, an organic solvent that is immiscible with water is added to the reaction mixture or a residue obtained by distilling the solvent of the reaction mixture, and the mixture is washed with water and the solvent is distilled off.
  • the obtained N-substituted phthalimide compound can be further purified by a conventional method, for example, recrystallization, reprecipitation, chromatography, or the like. ) May be used.
  • Examples of the solvent used in 2) in the above formula include: water; alcohols such as methanol, ethanol, and propanol; hydrocarbons such as petroleum ether, pentane, hexane, cyclohexane, benzene, and toluene; Ethers such as methyl ether, 1,2-dimethoxetane and tetrahydrofuran; nitriles such as acetonitrile and propionitrile; and N, N-dimethylformamide and ⁇ , ⁇ -dimethylacetamide Examples of such amides include alcohols (particularly, methanol) and nitriles (particularly, acetonitrile).
  • the reaction temperature varies depending mainly on the solvent used, but is usually in the range of room temperature to heating to reflux, preferably heating to reflux.
  • the reaction time varies depending on the 2-substituted phthalimide compound and the solvent used, but is usually 30 minutes to 24 hours, preferably 1 to 6 hours.
  • Amin compound having the formula R 4 a ⁇ ⁇ 2 can recovered from the reaction mixture by conventional methods. For example, after neutralization, an organic solvent that is not mixed with water is added to the residue obtained by distilling off the solvent of the reaction mixture or the reaction mixture, followed by washing with water and distilling off the solvent.
  • the obtained amine compound having the formula R 4 a NH 2 can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography, and is used in the A-14 step.
  • the solvent used in step A-4 is the starting compound There is no particular limitation as long as it dissolves (V) to some extent.
  • V dissolves
  • water alcohols such as methanol, ethanol, and propanol
  • petroleum ether pentane, hexane, cyclohexane, benzene, and toluene
  • Hydrocarbons such as, for example, ethers such as dimethyl ether, 1,2-dimethyloxetane, tetrahydrofuran; -tolyls, such as acetonitrile and propioetrile; and N, N-dimethylformamide, N, N-dimethyl.
  • Amides such as acetoamide.
  • alcohols (particularly methanol) and nitriles (particularly acetonitrile) are preferred.
  • Examples of the reducing agent used in the step A-4 include boron hydrides such as sodium cyanoborohydride.
  • the amount of the reducing agent to be used is generally 0.3 to 5 molar equivalents (preferably 1.5 to 3 molar equivalents) relative to compound (V).
  • Examples of the acid used in the step A-4 include mineral acids such as hydrochloric acid and sulfuric acid; carboxylic acids such as acetic acid and propionic acid; and sulfonic acids such as methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid. Of these, carboxylic acids (particularly acetic acid) are preferred.
  • the amount of the acid to be used is generally 0.3 to 3 molar equivalents (preferably 0.5 to 2 molar equivalents) relative to compound (V).
  • the amount of the amine compound R 4 a NH 2 used in the step A-4 is usually 0.5 to 3 molar equivalents (preferably 0.8 to 2 molar equivalents) with respect to the compound (V). ).
  • the reaction temperature varies depending on the compound and the solvent used, but is usually in the range of 0 to 50 ° C, and preferably room temperature.
  • the reaction time varies depending on the compound and the solvent used, but is usually 1 to 10 hours, preferably 2 to 4 hours.
  • compound (VI) can be collected from the reaction mixture by a usual method. For example, after neutralization, an organic solvent which does not mix with water is added to the reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washing with water and distilling off the solvent.
  • the obtained compound (VI) can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • This step is a step of producing an aldehyde compound (VII) by removing the protective group of the formyl group of the compound (VI) obtained in the step A-4.
  • This step is achieved by the formyl group deprotection reaction commonly used in organic synthetic chemistry (see column TW Greene et al., Protective Groups in Organic Synthesis, 2nd 'Edition, John Wiley & Sons, Inc. 1991)).
  • Examples of the solvent used include alcohols such as methanol and ethanol; ketones such as acetone; halogenated hydrocarbons such as dichloromethane and dichloroethane; or getyl ether, tetrahydrofuran, 1,4-dioxane, 1, Examples thereof include ethers such as 2-dimethyloxetane, and among them, alcohols (particularly, methanol) are preferable.
  • Examples of the acid used include mineral acids such as hydrochloric acid and sulfuric acid; sulfonic acids such as P-toluenesulfonic acid, methanesulfonic acid and camphorsulfonic acid; and carboxylic acids such as trifluoroacetic acid. Of these, mineral acids (particularly hydrochloric acid) are preferred.
  • the reaction temperature is usually in the range of 0 ° C to the boiling point of the solvent (preferably 0 ° C to room temperature), and the reaction time varies depending mainly on the protecting group to be removed. 4 hours (preferably 0.5 to 2 hours).
  • compound (VII) can be collected from the reaction mixture by a usual method. For example, after neutralization, the reaction mixture or a solvent obtained by distilling off the solvent of the reaction mixture is mixed with an organic solvent immiscible with water, washed with water, and the solvent is distilled off.
  • the obtained compound (VII) can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • This step is a step of producing the compound (la) of the present invention by removing the protecting group of the carboxyl group of the compound (VII) obtained in the step A-5.
  • This step is accomplished by a carboxyl group deprotection reaction commonly used in organic synthetic chemistry (eg, 'TW Greene et al., Protective Groups in Organic Synthesis, 2nd Edition, John Wiley & Sons, Inc. (1991) reference). For example, it is performed as shown in the following (1) and (2).
  • solvent used examples include water; alcohols such as methanol and ethanol; hydrocarbons such as hexane, cyclohexane, benzene and toluene; or getyl ether, tetrahydro; Ethers such as 1,4-dioxane and 1,2-dimethoxetane are preferred, and alcohols are preferred.
  • the catalyst examples include palladium catalysts such as palladium carbon, palladium black, and palladium hydroxide; platinum catalysts such as platinum oxide; and rhodium alumina And the like, and preferably a palladium catalyst (particularly, palladium hydroxide).
  • Examples of the hydrogen donor include hydrogen gas, formic acid, sodium formate, ammonium formate, and the like, with hydrogen gas being preferred.
  • the reaction temperature of the hydrogenolysis is usually from o ° C to room temperature, and the reaction time varies depending mainly on the protecting group to be removed, but usually from 5 to 24 hours (preferably from 0.5 to 24 hours). 2 hours).
  • compound (la) can be collected from the reaction mixture by an ordinary method. For example, it is obtained by removing the catalyst by filtration and distilling off the solvent of the filtrate.
  • R ′ 1 in the compound (VII) is an alkoxy-substituted benzyl group such as a methoxybenzyl or dimethoxybenzyl ′ group
  • the compound (VII) can be treated with an acid in a solvent or without a solvent.
  • the carboxylic acid compound (VI) or a salt thereof can be obtained also by treating with
  • solvent used examples include hydrocarbons such as hexane, cyclohexane, benzene, and toluene; halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane; and ethers such as anisol.
  • hydrocarbons such as hexane, cyclohexane, benzene, and toluene
  • halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane
  • ethers such as anisol.
  • halogenated hydrocarbons particularly, dichloromethane
  • the acid examples include mineral acids such as hydrochloric acid and sulfuric acid; sulfonic acids such as trifluoroacetic acid; and sulfonic acids such as trifluoromethanesulfonic acid. Of these, carboxylic acids (particularly trifluoroacetic acid) are preferred. is there.
  • the amount of the acid used varies depending on the kind of the acid and the kind of the solvent used, and is not particularly limited. For example, in the case of trifluoroacetic acid, it is usually used in an amount of 5 molar equivalents to the amount of the solvent based on the compound (VII). Preferably, it is used in an amount of 1/10 to 1/2 of the solvent used.
  • the reaction temperature of the acid treatment is usually from 0 ° C to room temperature, and the reaction time mainly depends on the type of the protecting group to be removed and the type and amount of the acid used.
  • trifluoroacetic acid is used as the acid in the group in a quarter amount of the solvent, it is usually 0.5 to 24 hours (preferably 0.5 to 2 hours).
  • compound (la) can be collected from the reaction mixture by a usual method. For example, after the reaction solution is concentrated, the residue is dissolved in water for neutralization, an organic solvent immiscible with water is added, washed with water, and the solvent is distilled off.
  • the compound (la) obtained by the above-mentioned various deprotection methods can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation, or mouth chromatography.
  • a conventional method for example, recrystallization, reprecipitation, or mouth chromatography.
  • Steps A-5 and A-6 of Method A described above may be performed in any order as shown in Method B.
  • R 1 is a formyl group
  • R 2 is a methyl group at the 7-position of a perhydro-1,4-oxazepine structure
  • R 3 is a perhydro-1,4-oxazepine structure.
  • R 4a , R ′ ⁇ and X 1 are as defined above.
  • step B-1 the carboxyl group of compound (VI) is deprotected to lead to compound (VIII)
  • step B-2 the formyl group of compound (VIII) is deprotected to give compound (la )
  • step B-2 the formyl group of compound (VIII) is deprotected to give compound (la )
  • This step is a step of producing compound (VIII) by deprotecting the carbonyl group of compound (VI) obtained in step A-4.
  • This step is achieved in the same manner as in step A-6 by a carboxyl group deprotection reaction generally used in organic synthetic chemistry.
  • This step is a step of producing a compound (la) by deprotecting the formyl group of the compound (VIII) obtained in the step B-1.
  • This step is achieved in the same manner as in the step A-5, by a formyl group deprotection reaction generally used in organic synthetic chemistry.
  • Method c is an intermediate compound used in method A (VII), in which a zofimarin derivative is used as a starting material, the formyl group is reduced without protecting the formyl group, the reaction is advanced, and the formyl group is subsequently restored by oxidation. ) Is separately produced, and is represented by the following reaction formula.
  • R 4 a and R '1 represents the same meaning as above, R, 2 is 1 to 4 double bonds which may have a C ⁇ C 1 0 Arukanoiru or Arukenoiru group der Alternatively, part or all of the double bond may be epoxidized.
  • the good suitable of R '2 may have 1 to 3 double bonds C - a Arukanoiru or Al Kenoiru group, particularly preferably 2, 4 - are to Kisajienoiru group.
  • This step is a step of producing an alcohol compound (X) by reducing the compound (IX).
  • the starting compound (IX) is described in JP-A-62-40292, J. Antibiot., 51, p. 41- (1998) or J. Antibiot., 51, p. 1012- (1998). It can be obtained by the method described or a method analogous thereto.
  • This step is achieved by reacting compound (IX) with a reducing agent in a solvent.
  • a solvent examples include water; alcohols such as methanol, ethanol and propanol; ethers such as getyl ether and tetrahydrofuran. Of these, preferred are etherenoles (particularly tetrahydrofuran). You.
  • reducing agent used examples include borohydrides such as sodium borohydride.
  • the amount of the reducing agent to be used is generally 0.3 to 5 molar equivalents (preferably 1 to 3 molar equivalents) relative to compound (IX).
  • the reaction temperature varies depending on the compound and the solvent used, but is usually in the range of 120 to 4, preferably 0 ° C to room temperature.
  • the reaction time varies depending on the compound and the solvent used, but is usually in the range of 0.5 to 24 hours, preferably 1 to 4 hours.
  • compound (X) can be collected from the reaction mixture by a usual method. For example, after neutralization, the reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture is added with an organic solvent immiscible with water, washed with water, and the solvent is distilled off.
  • the obtained compound (X) can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation, or chromatography.
  • This step is a step of producing a compound (XI) by protecting the carboxyl group of the compound (X) obtained in the C-11 step. ' This step is achieved in the same manner as in Step A-1 by a protective reaction of a lipoxyl group generally used in organic synthetic chemistry.
  • Step C-13 This step is a step of producing a 1,2-diol compound (XII) by removing the acyl group of compound (XI) obtained in step C-2.
  • This step is achieved by reacting compound (XI) with a base in a solvent.
  • a solvent examples include water; anoreconores such as methanol, ethanol and propanol; ethenoles such as getylether and tetrahydrofuran, and among them, alcohols (particularly methanol) are preferable.
  • the bases used are those commonly used in organic synthetic chemistry to remove the acyl group of the esters to give alcohols, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, hydroxide Metal hydroxides such as barium and calcium hydroxide; carbonates such as sodium carbonate and carbonated lime; alkoxides such as sodium methoxide, sodium methoxide and potassium t-toxide; sodium hydroxide and the like Thiolates can be mentioned. Of these, alkoxides (particularly sodium methoxide) are preferred.
  • the amount of the base to be used is generally 0.1 to 5 molar equivalents (preferably 0.2 to 1 molar equivalent) relative to compound (XI).
  • the temperature varies depending on the compound and the solvent used, and is usually in the range of from 20 to 40 ° C, preferably from 0 ° C to room temperature.
  • the reaction time varies depending on the compound and the solvent used, but is usually in the range of 0.5 to 24 hours, preferably 2 to 7 hours.
  • compound (XII) can be collected from the reaction mixture by a usual method. For example, after neutralization, the reaction mixture or a solvent obtained by distilling off the solvent of the reaction mixture is mixed with an organic solvent immiscible with water, washed with water, and the solvent is distilled off.
  • the obtained compound (XII) can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • This step is a step of oxidizing the compound (XII) obtained in the step C-4 to produce a dialdehyde compound (XIII). .
  • This step is achieved in the same manner as in Step A-3.
  • compound (XIII) can be collected from the reaction mixture by a usual method. For example, after neutralization, an organic solvent which does not mix with water is added to the reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washing with water and distilling off the solvent.
  • the formyl group of the dialdehyde compound (XIII) may form hydrates.
  • the dialdehyde compound (XIII) is usually obtained as an equilibrium mixture of compounds in which the formyl group is in such various association states, for example, due to formation of a hemi-acetal between them.
  • the obtained compound (XIII) can be purified to some extent by a conventional method, for example, reprecipitation or chromatography, but can be used for the next step without further purification.
  • the dialdehyde compound (XIII) the crude product obtained in the step C14 is usually used as it is. .
  • Amin compound having the formula R "NH 2 is obtained by the method shown in the description of the commercial as or a A- 4 step.
  • This step is accomplished in the same manner as in Step A-4.
  • compound (XIV) can be collected from the reaction mixture by a usual method. For example, after neutralization, the reaction mixture or a solvent obtained by distilling off the solvent of the reaction mixture is mixed with an organic solvent immiscible with water, washed with water, and the solvent is distilled off.
  • the obtained compound (XIV) can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • This step is a step of oxidizing the compound (XIV) obtained in Step C-15 to produce an intermediate compound (VII) used in Method A.
  • This step is achieved by reacting the alcoholic compound (XIV) with an oxidizing agent in an inert solvent.
  • the oxidizing agent used in the reaction is not particularly limited as long as it is an oxidizing agent used to oxidize an alcohol compound to an aldehyde compound in organic synthetic chemistry.
  • examples thereof include sulfoxides such as dimethyl sulfoxide; chromium trioxide; Chromium salts, oxides and complexes thereof, such as potassium dichromate, pyridinum chromatochromate and Collins reagent; ruthenium salts, such as ruthenium tetroxide and tetrapropylammonium perruthenate, oxides and complexes thereof; Lead salts such as lead oxide, oxides and complexes thereof; manganese salts such as potassium permanganate and manganese dioxide, oxides and complexes thereof; silver salts such as silver oxide and silver carbonate, oxides And complexes thereof; tungsten salts such as tungstic acid, oxides and complexes thereof; molybdenum salts such as molybdic acid, oxidation And complex
  • the amount of the oxidizing agent used in the reaction is usually 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to the alcohol compound (XIV).
  • the solvent used in the reaction is not particularly limited as long as the starting compound is dissolved to some extent and the reaction is not hindered.
  • water hydrocarbons such as hexane, cyclohexane, benzene and toluene; dichloromethane, dichloromethane Halogenated hydrocarbons such as mouth roethane; alcohols such as t-butyl alcohol; ketones such as acetone and 2-propanone; esters such as ethyl acetate; sulfoxides such as dimethyl sulfoxide; N, N-dimethylform Amides such as amides; nitriles such as acetonitrile; or ethers such as getyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxetane.
  • Preferred are water, hydrocarbons, halogenated hydrocarbons and ethers, and more preferred are halogenated hydrocarbons (particularly
  • the reaction temperature varies depending mainly on the oxidizing agent and the starting compound used, but it is usually in the range from 178 ° C to the boiling point of the solvent, preferably from 120 ° C to room temperature.
  • the reaction time varies depending mainly on the oxidizing agent, the starting compound and the reaction temperature, but is usually from 0.1 to 24 hours, preferably from 0.5 to 2 hours.
  • tetrapropylammonium perlute When tetrapropylammonium perlute is used as the oxidizing agent, tetrapropylammonium perlute is usually used in an amount of 0.01 to 0.1 mole equivalent, and the co-oxidizing agent is used.
  • Amines-oxides such as N-methylmorpholine-N-oxide are used in 1 to 5 molar equivalents, and a zeolite such as molecular sieves 4A is used as an additive in a weight ratio of 0.1 to 0.05% with respect to the compound (XIV). Add only 0.5.
  • the aldehyde compound (VII) can be collected from the reaction mixture by a usual method.
  • the reaction mixture is obtained by adding an organic solvent immiscible with water to the reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washing with water, and distilling off the solvent.
  • the obtained compound (VII) can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • Method D is as follows.
  • a compound (lb) in which R 3 is — ( 6 alkoxy) at the 6-position of the perhydro-1,4-oxazepine structure and R 4 is not a hydrogen atom It is a production method and is represented by the following reaction formula.
  • Step D Two steps Is in the main skeleton of compound (XV) or compound (XVI)
  • R ′ 3 and R ′ 4 represent a protecting group for an aldehyde
  • R ′ 5 represents a protecting group for a hydroxyl group
  • RR 2 , and R 4a have the same meaning as described above
  • R 3a is R 3 represents a C 6 -C 6 alkoxy at position 6 of the perhydro-1,4-oxazepine structure among R 3
  • L 1 represents a leaving group.
  • the protecting group R, 3 and R '4 represents a Asetaru of protecting groups used to one general the protection of aldehydes in synthetic organic chemistry, (e.g., TW Greene et al, Protective Groups m Organic Synthesis see 2nd Edition, John Wiley & Sons, Inc. (1991 years)), for example, methyl, Echiru, alkyl groups such as propyl; Ararukiru group such as a benzyl group; ⁇ Pi R '3 and R' 4 are together Alkylene groups such as ethylene and trimethylene are preferred. (Especially methinole and ethyl groups).
  • the protective group R '5 and shows generally coercive S ⁇ 3 ⁇ 4 used "to protect the hydroxyl groups in synthetic organic chemistry, (eg; L is, TW Greene 3 ⁇ 4, Protective Groups in Organic Synthesis, 2nd Edition, John Wiley & Sons, Inc. (1991)), although there is no particular limitation on the type, those which are stable under basic conditions and can be removed under acidic conditions are preferable.
  • the protective group include a carbonate-based protecting group. Of these, an etheric protecting group (particularly tetrahydroviranyl) is preferable.
  • the leaving group L 1 is a group which is eliminated in place of a nucleophile in a nucleophilic substitution reaction, for example, a halogen atom such as a chlorine atom, a bromine atom and an iodine atom; a methanesulfoninoleoxy group, a trifluoromethane Examples thereof include sulfonyloxy groups and sulfonyloxy groups such as toluenesnolephonyloxy group. Of these, a sulfonyloxy group is preferable, and a trifluoromethanesulfoninoleoxy group is more preferable.
  • the method is, first amine compound (XV) with an epoxide compound (XVI) is reacted leads to compound (XVII) (the D _ l step), then the alkyl and hydroxyl groups according to the type of radical R 3 a to be produced To the compound (XVIII) (Step D-2). Then, the protecting groups R 3 and R 4 of the formyl group and the protecting group R 5 of the hydroxyl group are removed to obtain the compound (XIX) (Step D-3). Step), further condensing with compound (XX) to give compound ( ⁇ ) (step D-4), and finally deprotecting the carboxyl group to produce compound (lb) (step D_5) It is a method.
  • This step is a step of producing a compound (XVII) by reacting the amine compound (XV) with the epoxide compound (XVI).
  • the starting amine compound (XV) can be easily produced by a method obvious to those skilled in the art.
  • a compound having the formula R 4a N is reacted with a commercially available compound having the formula Z 2 CH 2 CH (0R ′ 3 ) (0R M ) (Z 2 is a leaving group such as a bromine atom). can get.
  • the amine compound having the formula R 4 a NH 2 is commercially available or can be obtained by the method described in the description of Step A-4.
  • This step is achieved by heating the amine compound (XV) and the epoxide compound (XVI) in an inert solvent or without a solvent.
  • solvent used in the reaction examples include ethers such as tetrahydrofuran; amides such as ⁇ , ⁇ -dimethylformamide and ⁇ , ⁇ -dimethylformamide; nitriles such as acetonitrile; Sulfoxides such as sulfoxide and the like can be mentioned, and among them, amides are preferable.
  • This reaction usually proceeds only by mixing the oxime compound (XV) and the epoxide compound (XVI) and heating, but the progress can be accelerated by an additive.
  • the additive include lithium salts such as lithium chloride, lithium bromide, and lithium perchlorate; and Lewis acids such as tetraisopropoxytitanium and ytterbium trifluoromethanesulfonate.
  • the reaction temperature is usually in the range of 50 ° C. to 150 ° C., preferably 80 to 120 ° C.
  • the reaction time is usually in the range of 2 to 48 hours, preferably 4 to 20 hours.
  • compound (XVII) can be collected from the reaction mixture by a conventional method. For example, an organic solvent that is immiscible with water is added to the reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washed with water, and the solvent is distilled off.
  • the obtained compound (XVII) can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • This step is achieved by reacting the hydroxyl group of compound (XVII) with an alkylating reagent in a solvent in the presence of a base.
  • Solvents used for the alkylation include hydrocarbons such as hexane, cyclohexane, benzene, and toluene; ethers such as getyl ether and tetrahydrofuran; N, N-dimethylformamide; And amides such as N-dimethylacetamide; and sulfoxides such as dimethyl sulfoxide. Among them, amides (particularly N, N_dimethylformamide) are preferred.
  • Examples of the base used for the alkylation include metal hydrides such as lithium hydride, sodium hydride, and potassium hydride; methyllithium, and butyl Alkyl metals such as lithium; metal amides such as sodium amide, lithium dipropyl amide, and sodium hexamethyldisilazide, of which metal hydrides (particularly sodium hydride) are preferred. It is.
  • the amount of the base to be used is generally 1 to 2 molar equivalents relative to compound (XVII).
  • the alkyl reagent is a compound represented by the formula Z 3 —R 12 , and is derived from an alcohol compound represented by the formula HQ—R 12 or a hydrocarbon represented by the formula H—R 12 . It can be manufactured by a method. Wherein R 1 2 is a CFC 6 alkyl group, an alkyl moiety of the alkoxy group R 3 a in the compound are trying to manufacture (lb).
  • Z 3 is, for example, a halogen atom such as a chlorine atom, a bromine atom or an iodine atom; a sulfonyloxy group such as a methanesulfonyloxy group, a toluenesulfonyloxy group, or a trifnoroleolomethanesulfonyloxy group. Such a leaving group.
  • the amount of the alkylating reagent to be used is generally 1 to 3 molar equivalents relative to compound (XVII).
  • the reaction temperature for the alkylation is usually in the range of 110 ° C to the boiling point of the solvent, preferably 0 to 50 ° C.
  • the reaction time for the alkylation is usually in the range of 1 to 24 hours, preferably 2 to 10 hours.
  • compound (XVIII) can be collected from the reaction mixture by a conventional method. For example, an organic solvent that is immiscible with water is added to the reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washed with water, and the solvent is distilled off.
  • protection in the case where a hydroxyl group is protected in this step and removal of the protecting group in the step D-5 are achieved by a hydroxyl group protection reaction and deprotection reaction generally used in organic synthetic chemistry (for example, TW Greene et al.). , Protective Groups in Organic Synthesis, 2nd Edition, John Wiley & Sons, Inc. (1991)).
  • the obtained compound (XVIII) can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • This step is achieved by a formyl group and hydroxyl group deprotection reaction commonly used in organic synthetic chemistry (for example, TW Greene et al., Protective Groups in Organic Synthesis, 2nd Edition, John Wiley & Sons, Inc. (1991). Year)).
  • a formyl group and hydroxyl group deprotection reaction commonly used in organic synthetic chemistry (for example, TW Greene et al., Protective Groups in Organic Synthesis, 2nd Edition, John Wiley & Sons, Inc. (1991). Year)).
  • the formyl group or the hydroxyl group may be removed first, or they may be removed simultaneously.
  • this step is performed by reacting compound (XVIII) with an acid in a solvent. Achieved.
  • Examples of the solvent used include water; alcohols such as methanol and ethanol; ketones such as acetone; halogenated hydrocarbons such as dichloromethane and dichloroethane; or getyl ether, tetrahydrofuran,
  • Examples include ethers such as 4-dioxane and 1,2-dimethoxetane, and among them, alcohols (particularly, methanol) are preferable.
  • Examples of the acid used include mineral acids such as hydrochloric acid and sulfuric acid; sulfonic acids such as p-toluenesulfonic acid, methanesulfonic acid, and camphorsulfonic acid; and carboxylic acids such as trifluoroacetic acid. Of these, mineral acids (particularly hydrochloric acid) are preferred.
  • the reaction temperature is usually in the range of 0 ° C to the boiling point of the solvent (preferably 0 ° C to room temperature), and the reaction time varies depending mainly on the protecting group to be removed. 4 hours (preferably 0.5 to 2 hours).
  • the deprotected compound usually cyclizes in the molecule to a 7-membered ring compound (XIX).
  • compound (XIX) can be collected from the reaction mixture by a usual method. For example, after neutralization, the reaction mixture or a solvent obtained by distilling off the solvent of the reaction mixture is mixed with an organic solvent immiscible with water, washed with water, and the solvent is distilled off.
  • the obtained compound (XIX) can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • This step is a step of producing a compound (XXI) by condensing the compound (XIX) obtained in the step D-3 with the compound (XX).
  • Compound (XX) can be obtained by the method described in W099 / 58512 and J. M. Coteron et al. Tetrahedron Lett., 41, pp. 4373-4377 (2000).
  • the molar ratio of the compound (XIX) to the compound (XX) used is usually from 1: 2 to 2: 1, preferably from 3: 4 to 4: 3.
  • Examples of the solvent used include: hydrocarbons such as hexane and toluene; halogenated hydrocarbons such as dichloromethane and 1,2-dichloroethane; nitrogen-containing heteroaromatic compounds such as pyridine and lutidine; tetrahydrofuran; Ethers such as 4-dioxane and t-butyl methyl ether can be exemplified.
  • Examples of the base used include carbonates such as sodium carbonate, potassium carbonate and cesium carbonate; metal hydrides such as sodium hydride; and metal alkoxides such as potassium t-butoxide. The amount of the base used is 0.5 to 2 molar equivalents relative to compound (XX).
  • This step can be performed with an appropriate amount of additives to increase the yield and stereoselectivity. good.
  • additives include quaternary ammonium salts such as tetrabutylammonium triflate; zeolites such as molecular sieves 3A.
  • the reaction temperature varies depending on the compound and the solvent used, but is usually in the range of 0 to 40 ° C., and preferably room temperature.
  • the reaction time varies depending on the compound and the solvent used, but is usually in the range of 5 to 120 hours, preferably 20 to 100 hours.
  • compound (XXI) can be collected from the reaction mixture by a usual method. For example, after neutralization, the reaction mixture or a solvent obtained by distilling off the solvent of the reaction mixture is mixed with an organic solvent immiscible with water, washed with water, and the solvent is distilled off.
  • the obtained compound (XXI) can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. ,
  • the method is a method or analogous thereto according to 41, pp. 4373-4377 (2000) , the L 1 as the compound (XX) It can also be achieved by using an alcohol compound having a hydroxyl group and glycosylating it with compound (XIX). For example, it can be achieved by reacting a Lewis acid such as boron trifluoride ether complex, iron chloride (111), trimethylsilyl trifluoromethanesulfonate or the like in an inert solvent.
  • a Lewis acid such as boron trifluoride ether complex, iron chloride (111), trimethylsilyl trifluoromethanesulfonate or the like in an inert solvent.
  • This step is a step of deprotecting the carboxyl group of compound (XXI) obtained in Step D_4 to produce the compound (lb) of the present invention.
  • This step is achieved in the same manner as in Step A-6 by a carboxyl group deprotection reaction generally used in synthetic organic chemistry.
  • Method E is a method for producing a compound (Ic) in which R 4 is not a hydrogen atom among the compounds (I) of the present invention, and is represented by the following reaction formula.
  • R 2 and R 3 are the compound (XV) or the compound (XXII)
  • R '3, R' 4 , R '5, R ⁇ R 2, R 3, L ⁇ Pi R 4 a represents the same meaning as described above, L 2 represents a leaving group.
  • the leaving group L 2 is a group that leaves in place of a nucleophile in a nucleophilic substitution reaction, and is, for example, a halogen atom such as a chlorine atom, a bromine atom, or an iodine atom; methane snorehoninoleoxy And a sulfonyloxy group such as a trifluoromethanesulfonyloxy group and a toluenesulfonyloxy group. Of these, a sulfonyloxy group is preferred.
  • an amine compound (XV) is reacted with an alkylating agent (XXII) to obtain a compound (XXIII) (Step E-1), and then the formyl protecting groups R ′ 3 and R ′ 4 and the protecting group R '5 hydroxy groups by removing lead to compound (XXIV) (first E- 2 step), leading further to the compound (XX) and condensation with compound (XXV) (the E- 3 step), final Carboxyl group To produce compound (Ic) (Step E-4).
  • This step is a step of reacting the amine compound (XV) with the alkylating agent (XXII) to produce the compound (XXIII).
  • the starting amine compound (XV) can be easily produced by a method obvious to those skilled in the art. For example, it can be obtained by reacting a commercially available compound Z 2 CH 2 CH (OR ′ (compound having OR ′ (Z 2 represents a leaving group such as a bromine atom)) with an amine compound having the formula R 4 a NH 2 ., Amin compound having the formula R 4 a NH 2 is obtained by the method shown in the description of the commercial as or a A- 4 step.
  • the raw material of the alkylating agent (XXII) a method obvious to those skilled in the art, for example, the formula (R '5 0) CH 2 CH 2 CH sulfonylating Ya halogenation of the hydroxyl group of a compound having 2 0H, the formula (H0 ) It can be easily produced by protecting a hydroxyl group of a compound having CH 2 CH 2 CH 2 L 2 or the like.
  • This step is achieved by reacting the amine compound (XV) with the alkylating agent (XXII) in an inert solvent or in the absence of a solvent, usually in the presence of a base.
  • Solvents used in the reaction include, for example, ethers such as tetrahydrofuran; amides such as N, N-dimethylformamide and ⁇ , ⁇ -dimethylformamide; nitriles such as acetonitrile; dimethyl sulfoxide And the like. Of these, amides are preferable.
  • Examples of the base used in the reaction include carbonates such as potassium carbonate and sodium carbonate. '
  • the reaction temperature varies depending on the compound and the solvent used, but is usually in the range of room temperature to 150 ° C, and preferably in the range of room temperature to 80 ° C.
  • the reaction time varies depending on the compound and the solvent used, but is usually within a range from 2 to 48 hours, and preferably from 4 to 20 hours.
  • compound (XXIII) can be collected from the reaction mixture by a usual method. For example, an organic solvent that is immiscible with water is added to the reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washed with water, and the solvent is distilled off.
  • the obtained compound (XXIII) can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • This step is a step of producing compound (XXV) by condensing compound (XXIV) obtained in step E-2 with compound (X3 ⁇ 4).
  • Compound (XX) can be produced from the corresponding alcohol compound by the method described in W099 / 58512 or a method analogous thereto.
  • This step is accomplished in the same manner as in Step D-4.
  • This step is a step of producing the compound (Ic) of the present invention by deprotecting the carboxyl group of the compound (XXV) obtained in the step E-3.
  • Step A-6 This step is achieved in the same manner as in Step A-6 by a carboxyl group deprotection reaction generally used in synthetic organic chemistry. '
  • R 2 or R 3 is a hydroxyl group in the present method
  • the hydroxyl group is protected in compound (XV) or compound (XXII I) as a starting compound, and the protection is performed in step E-4.
  • the group may be removed.
  • the protection and removal of the protecting group in the case of protecting the hydroxyl group by this method can be achieved by the hydroxyl protecting and deprotecting reactions commonly used in organic synthetic chemistry (for example, TW Greene et al., Protective Groups in Organic Synthesis, 2nd Edition, see John Wiley & Sons, Inc. (1991) 0
  • Method F is a method for producing a compound (Id) in which R 4 is a hydrogen atom among the compounds (I) of the present invention, and is represented by the following reaction formula.
  • RR 2, R 3, and R '1 represents the same meaning as above, X 2 represents a formyl group, Shiano group or a protected formyl group, R 4 b is Ariru group (- alkyl ) May be substituted with a group. However, in this method, the carboxyl group may not be protected. In other words, - COzR 'I base - and C0 2 H based on a was also good casting.
  • the R 4 b for example, Ariru, 2 - Buteyuru, 3 - Mechirubuteyuru, 2 - methyl - 2 - Penteyuru group and the like, preferably these are Ariru group.
  • This step removes the (substituted) Ariru group R 4 b of the compound (XXVI), it is a step for preparing the compound (XVII).
  • This step is achieved by the deprotection reaction of the aryl group commonly used in organic synthetic chemistry (for example, TW Greeneb, Protective Groups in Organic Synthesis, 2nd Edition, p. 362, John Wiley & Sons , Inc. (1991)). That is, it can be achieved by reacting compound (XXVI) with a base or a metal catalyst or both in a solvent.
  • aryl group commonly used in organic synthetic chemistry for example, TW Greeneb, Protective Groups in Organic Synthesis, 2nd Edition, p. 362, John Wiley & Sons , Inc. (1991)
  • the solvent examples include water; alcohols such as methanol and ethanol; -tolyls such as acetonitrile; and sulfoxides such as dimethylsulfoxide.
  • Examples of the base include terminated T-lucoxides such as potassium t-butoxide; and amines such as 1,4-diazabicyclo [2.2.2] otatan.
  • Examples of the metal catalyst include Wilkinson Rhodium catalysts such as catalysts can be mentioned.
  • the reaction temperature is usually in the range of room temperature to the boiling point of the solvent, and is preferably 50 to 80 ° C.
  • the reaction time varies depending on the compound and the solvent used, but is usually in the range of 1 to 10 hours, preferably 2 to 4 hours.
  • the compound (XXVII) can be collected from the reaction mixture by a usual method, depending on the compound and the solvent used.
  • the reaction mixture or the reaction mixture An organic solvent that is immiscible with water is added to the residue obtained by distilling off the solvent, washed with water, and the solvent is distilled off.
  • the obtained compound (XXVII) can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • This step is a step of producing the compound (Id) of the present invention by removing the protecting group of the compound (XXVII) obtained in the F-1 step.
  • This step is achieved by a deprotection reaction generally used in organic synthetic chemistry (see, for example, T. W. Greene et al., Protective Groups in Organic Synthesis, 2nd Edition, John Wiley & Sons, Inc. (1991)). That is, it is achieved in the same manner as in the steps A-5, A-6, B-1, .B-2, D-5, and E-4.
  • Method G is a method for producing a compound (Ie) in which R 4 is not a hydrogen atom among the compounds (I) of the present invention by modifying a nitrogen atom in perhydro-1,4-oxazepine. It is shown by the reaction formula.
  • the method G has an advantage that if the compound (XXVII) as a starting material is synthesized, various compounds (I) of the present invention can be easily derived from the compound (XXVII).
  • RR 2 , R 3 , R 4a , X 2 , and R ′ 1 are as defined above. Is shown. However, in this method, the carboxyl group may not be protected. Immediate Chi, - C0 is 2 R, 1 group - C0 2 shall be H group.
  • This step is a step of producing compound (XXVIII) by alkylating compound (XXVII).
  • the starting compound (XXVII) is obtained by the F-1 step.
  • This step is achieved by reacting compound (XXVII) with an alkylating agent in an inert solvent or without solvent, usually in the presence of a base.
  • the alkylating agent of the formula R 4 a - is a compound having a Z 5, wherein Z 5 represents a leaving group, for example, a chlorine atom, a bromine atom, a halogen atom such as an iodine atom; methanesulfonic Norehoninore old alkoxy, Examples thereof include sulfonyloxy groups such as toluenesulfonyloxy and trifluoromethanesulfoninoleoxy.
  • Z 5 represents a leaving group, for example, a chlorine atom, a bromine atom, a halogen atom such as an iodine atom; methanesulfonic Norehoninore old alkoxy, Examples thereof include sulfonyloxy groups such as toluenesulfonyloxy and trifluoromethanesulfoninoleoxy.
  • Solvents used in the reaction include, for example, ethers such as tetrahydrofuran; amides such as ⁇ , ⁇ -dimethylformamide, ⁇ , ⁇ ⁇ ⁇ ⁇ -dimethylformamide; nitriles such as acetonitrile; dimethyl sulfoxide; And the like. Of these, amides are preferable.
  • Examples of the base used in the reaction include carbonates such as sodium bicarbonate, lithium carbonate, and sodium carbonate.
  • the reaction may be performed in the presence of an additive.
  • the additive include halogen salts such as sodium iodide, sodium bromide, tetrabutylammonium iodide and tetrabutylammonium bromide.
  • the amount of the additive to be added is not particularly limited, it is usually 0.1 mol in 2 mol equivalent with respect to the compound (XXVII).
  • the reaction temperature is usually in the range of room temperature to 150 ° C, preferably room temperature to 80 ° C. ⁇
  • the reaction time is usually in the range of 2 to 48 hours, preferably 4 to 20 hours.
  • compound (XXVIII) can be collected from the reaction mixture by a usual method. For example, an organic solvent that is immiscible with water is added to the reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washed with water, and the solvent is distilled off.
  • the obtained compound (XXVIII) may be used in a conventional manner if necessary, for example, by recrystallization, reprecipitation or It can be further purified by chromatography or the like.
  • This step can also be achieved, as an alternative, by a method of reducing compound (XXVII) with aldehydes and ketones. That is, it can also be achieved by reacting compound (XXVII) with an aldehyde / ketone with a reducing agent in the same manner as in the step A_4.
  • This step is a step of producing the compound (Ie) of the present invention by removing the protecting group of the compound (XXVII I) obtained in the G-1 step.
  • This step is achieved by a deprotection reaction generally used in organic synthetic chemistry (see, for example, TW Greene et al., Protective Groups in Organic Synthesis, 2nd Edition, John Wiley & Sons, Inc. (1991)). . That is, it is achieved in the same manner as in the steps A-5, A-6, B-1, B-2, D-5, E-4, and F-2.
  • Method H is a method for producing a compound (If) in which R 1 is a cyano group and R 4 is not a hydrogen atom among the compounds (I) of the present invention by converting a formyl group to a cyano group. Is shown by the following reaction formula.
  • R 2 , RR 4 a , and R ′ 1 have the same meaning as described above.
  • this method first, the formyl group of the compound (XXIX) is converted to a cyano group, and the compound (XXX) IZ Derivation (Step H-1), and then removing the protecting group to give compound (If) (Step H-2).
  • This step is a step of converting the formyl group of compound (XXIX) to a cyano group to produce compound (XXX).
  • the starting compound (XXIX) can be prepared according to Method A, Method C, Method D, Method E, Method G or Method J described below, and the intermediate compound or the final compound of the method (that is, Compound (VII), (XXI ), (XXV), (XXVIII), or (XXXIII)).
  • This step is achieved by a conversion reaction of an aldehyde to a nitrile, which is commonly used in organic synthetic chemistry.
  • a conversion reaction of an aldehyde to a nitrile which is commonly used in organic synthetic chemistry.
  • IT Harrison et al. Compendium of Organic Synthetic Methods, pp. 460-464, Wiley Interscience (1971), W099 / 09974, W099 / 09975, and B. Tse et al. Bioorg. Med. Chem. Lett. , 8, pp. 2269-2272 (1998).
  • This step is a step of preparing the compound (If) of the present invention by removing the protecting group of the compound (XXIX) obtained in the H-1 step.
  • This step is achieved by a deprotection reaction commonly used in organic synthetic chemistry (see, for example, T. W. Greene et al., Protective Groups m Organic Synthesis, 2nd
  • Method J is a method for producing a compound (Ig) in which R 3 is a hydroxyl group among the compounds (I) of the present invention, and is represented by the following reaction formula.
  • R ′ 6 is a protecting group.
  • the protecting group R '6 is a protected hydroxyl group in synthetic organic chemistry represents a protecting group used to one general (eg, TW Greene et al, Protective Groups in Organic Synthesis, 2nd Edition, John Wiley & Sons, Inc. (1991)).
  • TW Greene et al Protective Groups in Organic Synthesis, 2nd Edition, John Wiley & Sons, Inc. (1991)
  • the acyl group of compound (XXXI) is removed to lead to compound (XXXII) (Step J-11), and then the protecting group is removed to obtain compound (Ig) (Step J-12) In a way. ,
  • This step is a step of producing compound (II) ′ by removing the acyl group of compound (XXXI).
  • the starting compound (XXXI) is an intermediate compound or a final compound (that is, compound (XXI), (XXV), (XXVIII), (XXXIII), Alternatively, it can be manufactured as (XXX)).
  • This step is achieved by reacting compound (XXXI) with a base in a solvent in the same manner as in Step C-13.
  • Step J-1 two steps This step is a step of producing the compound (If) of the present invention by removing the protecting group of the compound (XXIX) obtained in the J_1 step.
  • This step is achieved by the deprotection reaction commonly used in synthetic organic chemistry.
  • the pharmacologically acceptable ester of the zofimarin derivative according to the present invention is a synthetic intermediate in each of the above-mentioned methods A to J (for example, compounds (VII), (XXI) s (XXV), (XXVII), (XXVIII) ), (XXX), (XXXII)), or by introducing the desired compound in each of the above-mentioned methods (1) to (J) into a desired ester by a method obvious to those skilled in the art.
  • the pharmacologically acceptable salt of the zofimarin derivative or the pharmacologically acceptable ester thereof according to the present invention may be obtained as a target product or a synthetic intermediate in each of the methods A to J described above, It can also be obtained by introducing the target compound or synthetic intermediate in each method to a desired salt by a method obvious to those skilled in the art.
  • the zofimarin derivative of the present invention, its pharmacologically acceptable ester, and its pharmacologically acceptable salt include Candida spp., Aspergillus spp., Talipococcus spp., Mucor spp., Histoplasma spp., Plastomyces spp., Coccidioides spp.
  • zofimarin derivatives and their pharmacologically acceptable esters and their A pharmacologically acceptable salt can be used as a medicament (preferably an antifungal agent, more preferably an anti-Candida fungus agent).
  • a medicament preferably an antifungal agent, more preferably an anti-Candida fungus agent.
  • it may be used alone or mixed with appropriate pharmacologically acceptable excipients, diluents, etc., orally or in tablets, capsules, granules, powders or syrups. It can be administered parenterally by injection or the like.
  • excipients eg, sugars such as lactose, sucrose, glucose, mannitol, sorbitol; starch derivatives such as corn starch, potato starch, ⁇ -starch, dextrin, carboxymethyl starch; Crystalline cellulose, low-substituted hydroxypropylcellulose, hydroxypropinolemethinoresenorelose, olenoxoxymethinoresenorelose, canoleboxymethinoresenorelose calcium, internally-crosslinked sodium carboxymethylcellulose sodium Dextran; pullulan; silicates such as light silicic anhydride, synthetic aluminum silicate, magnesium metasilicate, magnesium phosphate; phosphates such as calcium phosphate; carbonates such as calcium carbonate '; Sulfuric acid Sulphates such as sodium chloride, binders (for example, the above-mentioned excipients; gelatin; polybulpyrrolidone; magrogol, etc.); disintegrants (for example,
  • the dosage varies depending on symptoms, age, etc., but in the case of oral administration, for adults, the lower limit is 1 mg / day (preferably 5 mg) and the upper limit is 200 mg / day (preferably 10 mg / day). In the case of intravenous administration, it is desirable to administer a lower limit of 0.1 mg (preferably 0.5 mg) per day and an upper limit of 60 Omg (preferably 50 Omg) per day. The administration can be divided into 1 to 6 times depending on the symptoms.
  • sordarin i.e., [1R - (l G; , 3aJS, 4 J ⁇ , 4aiS, 7iS, 7a ⁇ , 8ai3)] - 8a- [[(2R, 3S, 4S, 5S, 6R) - 3, 4 -Dihydroxy-5-methoxy-6-methyl-3,4,5,6-tetrahydro (2H) pyran-2-yl] oxymethyl] -4-forminole-3-isopropyl-7-methyl- 4,4a, 5,6,7,7a, 8,8a-octahydro-1,4 methano-s-indacene-3a (lH) -carbonate zofimarin (described in JP-A-62-40295, To a 6 g, 4.4 mm o 1) methanol solution (50 ml), add a 28% methanol solution of sodium methoxide (1.8 ml, 8.8 mm o 1) at room temperature.
  • the reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate, and extracted twice with ethyl acetate (50 ml). The organic layers were combined, washed with water (30 ml) and saturated saline (30 ml), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue.

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Abstract

L'invention concerne des dérivés de zofimarin présentant une excellente activité antifongique, des esters et des sels de ceux-ci acceptables sur le plan pharmaceutique; des compositions médicales (notamment, des agents antifongiques) renfermant ceux-ci comme principe actif; l'utilisation de ces dérivés, de ces esters et de ces sels destinés à la production de ces compositions médicales; ainsi qu'une méthode de prévention ou de traitement de maladies (notamment des infections fongiques) consistant à administrer une dose efficace sur le plan pharmaceutique de ces dérivés, de ces esters ou de ces sels, en vue de chauffer des animaux (notamment l'être humain) présentant un système sanguin. Les dérivés de zofimarin, tels que décrits ci-dessus, sont représentés par la formule générale suivante (I): dans laquelle R1 représente un formyle, etc.; R2 et R3 représentent, de manière indépendante, un alkyle en C¿1-6?; et R?4¿ représente un hydrogène.
PCT/JP2001/007925 2000-09-13 2001-09-12 Dérivés de zofimarin présentant un noyau oxazépame WO2002023541A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001286208A AU2001286208A1 (en) 2000-09-13 2001-09-12 Zofimarin derivatives having oxazepam ring

Applications Claiming Priority (2)

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JP2000-277434 2000-09-13
JP2000277434 2000-09-13

Publications (1)

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WO2002023541A1 true WO2002023541A1 (fr) 2002-03-21

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PCT/JP2001/007925 WO2002023541A1 (fr) 2000-09-13 2001-09-12 Dérivés de zofimarin présentant un noyau oxazépame

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AU (1) AU2001286208A1 (fr)
WO (1) WO2002023541A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6240292A (ja) * 1985-08-14 1987-02-21 Sankyo Co Ltd 抗生物質ゾフイマリン
WO1999058512A1 (fr) * 1998-05-11 1999-11-18 Glaxo Wellcome S.A. Ethers de morpholine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6240292A (ja) * 1985-08-14 1987-02-21 Sankyo Co Ltd 抗生物質ゾフイマリン
WO1999058512A1 (fr) * 1998-05-11 1999-11-18 Glaxo Wellcome S.A. Ethers de morpholine

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